Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)

Brief Title

Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)

Official Title

Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis (Re-Launch)

Brief Summary

      Transverse myelitis (TM) is an inflammatory disorder of the spinal cord that leads to
      disabilities of gait. Dalfampridine, a sustained-release potassium inhibitor has been shown
      to be effective in improving gait and other neurologic functions in multiple sclerosis.
      Dalfampridine has the potential to improve neurologic function in patients with transverse
      myelitis as this rare disorder shares a similar pathogenic process with multiple sclerosis.
      The in a clinical trial to test the efficacy of dalfampridine in TM.

      The clinical trial that the investigators propose to conduct will focus on TM and will
      evaluate the dalfampridine in primary neurologic outcome, 25-foot timed walk, and several
      secondary outcomes including valid behavioral and neurophysiological tests.

      This is a re-launch of the previous trial, which now includes additional behavioral and
      clinical testing.
    

Detailed Description

      Fampridine (4-aminopyridine) is a potassium channel blocker that has been studied since the
      1970s for its effect on amplifying conductivity in peripheral nerves, potentiating
      neurotransmitter release in muscles and increasing post-synaptic action potentials in the
      spinal cord. It was tested in other neurologic conditions over the next two decades and was
      found to have a limited therapeutic window due to the stimulation of seizures at high doses.
      The first randomized, placebo-controlled, double-blinded study of fampridine in 70 patients
      found significant improvements in a number of neurophysiological parameters while on
      fampridine compared to placebo. Since then, at least six additional studies on oral
      fampridine in Multiple Sclerosis (MS) were conducted and found to have some significant
      neurologic function. Although only a small incidence of seizure or altered mental status were
      reported in these studies, the concern about fampridine causing seizures remained a barrier
      in the acceptance of fampridine as an MS therapy in the general neurology community.

      Recently, Biogen-Idec and Acorda have teamed up in the development of a sustained-release
      formulation of fampridine, dalfampridine, in which plasma concentrations of the drug and
      avoids toxic doses that lead to seizures. In two clinical trials, dalfampridine has been
      shown to be beneficial in two large cohorts of multiple sclerosis patients with noted
      improvements in gait and lower extremity muscle strength. Seizures were only seen in high
      doses of 20 mg or more whereas benefits were evident at the approved dose of 10 mg twice
      daily.

      The Food and Drug Administration (FDA) approved dalfampridine for use in multiple sclerosis
      in 2009 based on the key study that evaluated gait by timed 25-foot walk. About 35-40% of
      study participants responded and this group improved their walking speed by about 20%.

      The investigator's interest in dalfampridine is focused more narrowly on a subset of patients
      with a demyelinating disorder that is restricted to the spinal cord, transverse myelitis
      (TM), was not included in any previous human trials of dalfampridine. In contrast to MS,
      which affects the entire system, transverse myelitis affects the spinal cord and largely
      spares the brain. It is not associated with an increased risk of seizure.

      Transverse myelitis is defined as an episode of inflammation in the spinal cord leading to
      disability at the level of the lesion and below. The majority of TM lesions strike the
      thoracic cord causing impairments in lower extremities. A single lesion is the cause of all
      of their symptoms. The goal of using dalfampridine in these patients is to amplify axonal
      conductance across the lesion. This would manifest as improved neurologic function involving
      the lower extremities including gait. This is a straightforward proof of concept model
      proving the mechanism of action of dalfampridine.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Walking Speed During Timed 25-foot Walk

Secondary Outcome

 Upper and Lower Extremity Muscle Strength Measurements

Condition

Transverse Myelitis

Intervention

Dalfampridine

Study Arms / Comparison Groups

 Dalfampridine then Placebo
Description:  All subjects were randomized for the first double-blinded 8-week part of the study to the dalfampridine group. Then subjects were crossed over to the placebo arm for another 8 weeks.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

February 2014

Completion Date

January 8, 2017

Primary Completion Date

January 8, 2017

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of transverse myelitis confirmed by MRI

          -  Gait impairment defined as a baseline timed 25-foot walk of at least 5 seconds and no
             more than 60 seconds.

          -  Age 18-70.

        Exclusion Criteria:

          -  Diagnosis of any of the following concurrent conditions: spinal dural arteriovenous
             malformation, multiple sclerosis, infectious myelitis and recurrent transverse
             myelitis of any etiology. Subjects with a positive NMO-Immunoglobulin G (IgG)
             biomarker test will be permitted to join the study as long as the there is only a
             history of monophasic, and not recurrent, TM.

          -  History of seizure(s).

          -  Pregnancy or positive pregnancy test (mandatory test for all women aged 18-55 to be
             done at first screening visit).

          -  Known use or allergy to dalfampridine or any other formulation of 4-aminopyridine.

          -  Patients unable to walk.

          -  Patients with history of severe alcohol or drug abuse, severe psychiatric illness such
             as severe depression, poor motivational capacity, or severe language disturbances,
             particularly of receptive nature or with serious cognitive deficits (defined as
             equivalent to a mini-mental state exam score of 23 or less).

          -  Patients with severe uncontrolled medical problems (e.g. hypertension, cardiovascular
             disease, severe rheumatoid arthritis, active joint deformity of arthritic origin,
             active cancer or renal disease, any kind of end-stage pulmonary or cardiovascular
             disease, claudication, uncontrolled epilepsy or others).
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Michael Levy, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02166346

Organization ID

NA_00090799


Responsible Party

Sponsor

Study Sponsor

Johns Hopkins University

Collaborators

 Acorda Therapeutics

Study Sponsor

Michael Levy, MD, PhD, Principal Investigator, Johns Hopkins University


Verification Date

March 2018